The current upswing in the abuse of methamphetamine, 3,4- methylenedioxymethamphetamine (MDMA; "ecstacy") and related compounds follows closely on the heels of an epidemic of cocaine abuse. An increased incidence of adverse consequences associated with cocaine use has generated investigations of its mechanisms of action; one goal of such studies is to identify pharmacological agents which can block or reverse its psychotropic and toxic effects. Much of this research has focussed on the importance of dopamine (DA) and norepinephrine (NE) in mediating the many and varied physiological and psychological effects attributed cocaine. However, in addition to actions on DA and NE, cocaine also interferes with serotonin (5-hydroxytryptamine; 5-HT) function. Since cocaine abusers experience physiological disorders (anorexia and hyposomnia) as well as psychiatric disorders (anxiety, depression and psychoses) in which 5-HT has been implicated, specific alterations in 5-HT function may underlie some cocaine pharmacology. These psychiatric consequences probably are mediated in part by limbic structures, such as the amygdala and nucleus accumbens, which also receive significant afferent projections from 5-HT containing neurons of the dorsal raphe. Observational procedures will be used to study 5-HT receptor modulation of cocaine-induced hyperactivity and stereotypy and the hypothesis that repeated exposure to cocaine may elicit lasting alterations in 5-HT function will be measured using two behavioral models of 5HT stimulation. Groups of rats will also be trained to discriminate cocaine from saline in two- or three-lever drug discrimination tasks; in three-lever situations, the second drug will be pharmacologically similar to cocaine (e.g., DA reuptake inhibitor or local anesthetic). Substitution, potentiation and antagonism tests with selective 5-HT compounds will help to identify the importance of this system in the subjective state induced by cocaine. We will investigate the dorsal raphe and two limbic sites (amygdala, nucleus accumbens) as possible anatomical substrates of the cocaine cue using microinjection and neurotoxin lesion techniques. Importantly, these studies will provide new insights into the mechanisms responsible for the physiological and psychological effects of cocaine and how these compare to other stimulants. This knowledge is essential to the development of novel approaches to stimulant antagonism and pharmacological treatment strategies for abusers.